Photoinduced Reaction Synthesis Of Isoindolinone Bridged Cycloheptapeptide Combined With Quantum Chemical Calculations

As one of the most important biomolecules in natural world,cyclic peptides have attracted great attention due to their diverse structures,low inherent toxicity,high selectivity and affinity for binding protein targets and rich functions.Compared with their linear counterparts,due to the lack of both amino and carboxyl terminals,the resistant to endopeptidases,exceptionally high stability,stronger cell permeability and potent biological activity make them valuable resources in drug discovery.This article aims to screen natural cyclic peptides with antitumor activity and synthesize their natural cyclic peptide analogs through photoinduced single electron transfer（SET）reaction,investigating their antitumor activity difference and the stereostructure of modified cyclic peptide analogs,screening for high antitumor activity compounds and discussing their structure-activity relationship.Firstly,a natural cyclic peptide with antitumor activity Yunnanin A was chioced as the leading compound and its analog was synthesised by intramolecular photoinduced SET reaction.The stereostructure was determined by electronic circular dichroism（ECD）combined with theoretical calculations and the MTT assay was used to test its antitumor activity.Then another natural antitumor cyclic peptide Phakellistatin 13 was chioced as the leading compound and a series of its analogs were synthesised by intramolecular photoinduced SET reaction.By changing the confomer of the amino acid residues,connection sequence and the inserted position of Phthalimide fragment,the MTT assay was carried out on those analogs and their stereostructure was studied by ECD combined with theoretical calculations.In addition,based on the study of the absolute configuration of the chiral fetures of the cyclic peptide compounds,this article also plans to obtain the chiral information of some small molecule drugs with chiral ring structure by ECD combined with quantum chemistry calculations,and explore the research method of those compounds possess chiral ring structure.Basing on this,detailed electronic and structural information of these molecules can be obtained by quantum chemical calculations.For this reason,two chiral drugs Crizotinib and Loratinib targeted non-small cell lung cancer were selected.Through conformation search,the obtained energy-lower conformation was used to calculate the geometric structure,Mulliken charge distribution,molecular electrostatic potential,vibration frequency,infrared intensity,ECD spectrum,¹H and ¹³C-NMR spectrum and other properties of the molecule by DFT/B3LYP/6-311++G（d,p）method,and compared with the experimental results.Finally,the frontier molecular orbital（FMOs）analysis and the global descriptors were also carried out.